Variant 10-96527219-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000371142.9(TM9SF3):c.1696A>T(p.Met566Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TM9SF3
ENST00000371142.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.92

Variant links:

Genes affected

TM9SF3 (HGNC:21529): (transmembrane 9 superfamily member 3) Predicted to be involved in protein localization to membrane. Predicted to be located in exocytic vesicle. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

TM9SF3 links:

TM9SF3 (HGNC:):

TM9SF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33098572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM9SF3	NM_020123.4 linkuse as main transcript	c.1696A>T	p.Met566Leu	missense_variant	14/15	ENST00000371142.9	NP_064508.3	Q9HD45A0A024QYS2
TM9SF3	XM_011539976.3 linkuse as main transcript	c.1750A>T	p.Met584Leu	missense_variant	14/15		XP_011538278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TM9SF3	ENST00000371142.9 linkuse as main transcript	c.1696A>T	p.Met566Leu	missense_variant	14/15	1	NM_020123.4	ENSP00000360184.4	Q9HD45
TM9SF3	ENST00000485093.1 linkuse as main transcript	n.347A>T		non_coding_transcript_exon_variant	3/4	5
TM9SF3	ENST00000649367.1 linkuse as main transcript	n.2034A>T		non_coding_transcript_exon_variant	14/15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249530

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1456008

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.1696A>T (p.M566L) alteration is located in exon 14 (coding exon 14) of the TM9SF3 gene. This alteration results from a A to T substitution at nucleotide position 1696, causing the methionine (M) at amino acid position 566 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.028

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.028

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.014

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.17

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.95

REVEL

Benign

0.21

Sift

Benign

0.55

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.62

MutPred

0.42

Loss of helix (P = 0.1299);

MVP

0.63

MPC

0.90

ClinPred

0.62

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over